Innate immune regulation of infection tolerance

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All living organisms have immune responses to protect them from infections. We regard these immune responses as working in two basic ways: "resistance" responses protect the host by killing invaders, while "tolerance" responses protect the host by preventing damage caused by infection. These two types of response must work together: resistance without tolerance cannot keep us alive in the presence of many pathogens, while tolerance without resistance will result in an increase in both the abundance and proliferation of pathogens, leading to infections against which our immune systems will be defenseless . Many resistance mechanisms are relatively well-understood, but we know very little about how infection tolerance works. For example, even though tolerance has been cited as a potential therapeutic intervention, we still don't know whether tolerance is generally activated by immune responses ("inducible" tolerance), or if tolerance is a pre-existing state. We also don't understand how tolerance and resistance work together in controlling infections and keeping the host healthy.In our lab, we study the immune response of the fruit-fly Drosophila melanogaster to bacterial infection. The fruit-fly's immune response is similar in many ways to those of humans and other mammals, but because flies are small, inexpensive, and have a short generation time, we can study immune responses to infection in the whole animal in ways that are impossible in mammals. We have recently discovered that flies with a genetic mutation in a "resistance" gene also have a serious defect in infection tolerance: when these mutants are infected with pathogenic bacteria, they die significantly sooner than non-mutant flies, but show no difference in terms of resistance (mutants and non-mutants contain the same number of bacteria). Thus, the immune response of these flies suggests that tolerance may be an inducible trait. This is very exciting because it allows us to identify the mechanisms of tolerance that are being activated by this gene.The experiments we propose will focus on three aspects of this tolerance effect. First, we will measure metabolic and behavioural differences between mutant and non-mutant flies during infection. This is important because metabolic control and behaviour have been suggested to be critical determinants of tolerance, but we don't really have any grasp on how these two things would be different between tolerant and non-tolerant hosts. Second, we will test the roles of related genes in affecting tolerance, and determine which tissues these genes are functioning in to promote infection tolerance. This is important because it will give us insight into the mechanisms of tolerance induction, as well as allow us to determine to what extent tolerance is determined by host genetics. Finally, we will use this information and information on genes turned on by infection, to identify the genetic mechanisms of tolerance induction. This is important because it will let us know the specific mechanisms that can promote tolerance in the host, separate from effects on resistance.This work may ultimately lead to the ability to promote tolerance in people with infections. Therapies that promote tolerance would be useful to allow the immune system or antibiotics time to work. Thus, we hope that our analyses of infection biology in fruit flies will give us information that will ultimately be useful in the treatment of human disease.